Substituted anilino-2-thiazolines

ABSTRACT

Novel para-polyfluoroisopropyl-anilino-2-oxazolines and thiazolines are provided which exhibit potent antihypertensive properties without significant CNS depression.

This is a division of application Ser. No. 668,385, filed Mar. 19, 1976,now U.S. Pat. No. 4,081,547 which, in turn, is a continuation-in-part ofmy copending application Ser. No. 528,603, filed Dec. 2, 1974, which ishereby incorporated by reference now abandoned.

This invention relates to novelpara-polyfluoroisopropyl-anilino-2-oxazolines and the corresponding2-thiazolines which are useful in the treatment of mammalianhypertension. Used as such, they exhibit high potency with little or nodepression of the central nervous system.

These compounds may be represented by the structural formula: ##STR1##wherein X is an oxygen or sulfur atom,

R is alkyl having 1 to 4 carbon atoms,

R₁, r₂ and R₃ are independently hydrogen, bromine, chlorine, fluorine,lower alkyl, lower alkoxy, lower alkanoyloxy or nitro,

Y, y₁, y₂ and Y₃ are independently hydrogen, chlorine or fluorine,

Z is independently hydrogen, hydroxy, lower alkoxy, lower alkanoyloxy,chlorine or fluorine.

The term "lower" as used in the above definitions means that the alkylportion of the subject group contain 1 to 6 carbon atoms. In the case of"lower alkanoyloxy" this portion contains 2 to 6 carbon atoms.

Within the broad scope of Formula I there are, of course, certainpreferential embodiments. R₃ is preferably hydrogen. R₁ and R₂ arepreferentially hydrogen or lower alkyl. R₁ and R₂ each being a loweralkyl group is a preferred embodiment. Z is preferably a hydroxy group.

X is preferably an oxygen atom, i.e. an oxazcline. A highly preferredcompound is2-[4-(hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline. Otherpreferred oxazolines within the scope of this invention include:

2-[4-(tetrafluoro-1,3-dichloro-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline

2-[4-(hexafluoro-2-methoxy-2-propyl)-N-methylanilino]-2-oxazoline

2-[N,2,6-trimethyl-4-(hexafluoro-2-hydroxy-2-propyl)anilino]-2-oxazoline

2-[4-(hexafluoro-2-hydroxy-2-propyl)-2-chloro-N-methylanilino]-2-oxazoline

2-[4-(hexafluoro-2-hydroxy-2-propyl)-N,2-dimethylanilino]-2-oxazoline

2-[4-(hexafluoro-2-hydroxy-2propyl)-N-n-propylanilino]-2-oxazoline

2-[2,6-diisopropyl-4-(hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline

2-[4-(1,1,1-trifluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline

2-[4-(3-chloropentafluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline

2-[4-(2-acetoxyhexafluoro-2-propyl)-N-methylanilino]-2-oxazoline

2-[4-(2-chlorohexafluoro-2-propyl)-N-methylanilino]-2-oxazoline

2-[2,6-dichloro-4-(hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline

2-[2,6-diethyl-4-(hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline

2-[2-chloro-4-(hexafluoro-2-hydroxy-2propyl)-N,6-dimethylanilino]-2-oxazoline

2-[4-(hexafluoro-2-hydroxy-2propyl)-2-methoxy-N-methylanilino]-2-oxazoline

2-[2-fluoro-4-(hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline

2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,5-dimethyl-N-methylanilino]-2-oxazoline

2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethoxy-N-methylanilino]-2-oxazoline

2-[N-ethyl-4-(hexafluoro-2-hydroxy-2-propyl)anilino]-2oxazoline

2-[4-(hexafluoro-2-propyl)-N-methylanilino]-2-oxazoline

A preferred thiazoline is2-[4-(hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-thiazoline.Other thiazolines within the scope of this invention includes:

2-[4-hexafluoro-2-hydroxy-2-propyl)-N-ethylanilino]-2-thiazoline

2-[N,2,6-trimethyl-4-(hexafluoro-2-hydroxy-2-propyl)anilino]-2-thiazoline

2-[4-(tetrafluoro-1,3-dichloro-2-hydroxy-2-propyl)-N-methylanilino]-2-thiazoline.

Similarly, the other oxazolines listed above have correspondingthiazolines within the scope of this invention.

The above oxazolines and thiazolines of Formula I may be administeredper se or in the form of their pharmaceutically acceptable acid additionsalts. Exemplary of the latter are those formed with maleic, acetic,phthalic, succinic, lactic, tartaric, citric, malic, cinnamic,methane-sulphonic, hydrochloric, hydrobromic, sulfuric and phosphoricacids. The salts may be prepared by the standard technique ofprecipitation by treatment of a solution of the free base in a suitableorganic solvent with the desired acid. Further purification, if desired,may be effected by recrystallization.

The art, in retrospect, discloses that other substitutedanilino-2-oxazolines have hypotensive activity, e.g. U.S. Pat. Nos.3,453,284; 3,499,083 and 3,499,084 and Belgian Pat. Nos. 704,392;704,393 and 704,396. However, in these prior art oxazolines the anilinenitrogen atom is unsubstituted and the critical para-polyfluoroisopropylphenyl substituent is not suggested. Moreover, these compounds aretaught to be central nervous system depressants.

Similarly, the art discloses that polyfluoroisopropyl-substitutedanilines are known and in some cases reported to have hypotensiveactivity, e.g. U.S. Pat. Nos. 3,405,177; 3,541,152; 3,594,418; 3,772,273and Gilbert, J. Org. Chem., Vol. 30 (1965) 1001. The compounds of myinvention exhibit much more potent and useful hypotensive activity thando the foregoing anilines. Those compounds of Formula I wherein X isoxygen can be prepared by the intramolecular condensation of a urea ofFormula II: ##STR2## wherein R, R₁, R₂, R₃, Y, Y₁, Y₂, Y₃ and Z are asabove defined and T is a labile leaving group such as halogen, or asulfonic acid ester moiety; e.g. tosyl and mesyl. Chlorine is thepreferred T group. The condensation can be effected by heating the ureain an aqueous alcoholic vehicle, preferably under acidic conditions. Theurea of Formula II can in turn be prepared by methods described in mycopending patent application Ser. No. 528,603; and other methodsdescribed in the literature such as the above-cited patents.

Those compounds of Formula I wherein X is sulfur can be directlyprepared by the condensation of chloro- or bromo- ethylisothiocyanatewith the corresponding aniline of Formula III: ##STR3## wherein R, R₁,R₂, R₃, Y, Y₁, Y₂ and Z are as above defined. The two reactants arerefluxed in an inert solvent, e.g. benzene, and the correspondingthiazoline hydrohalide is removed and purified in the conventionalmanner.

The following examples illustrate the preparation of representativecompounds of my invention.

EXAMPLE 12-[4-(hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline

Dissolve 10.0 g (26 m.mole) ofN-(2-chloroethyl)-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-N'-methyl-ureain a mixture of 50 ml of methanol and 100 ml of water. Heat for one houron a steam bath. Concentrate, and partition between 1N aqueous sodiumbicarbonate solution and ether (diethyl) and then extract with 200 ml of1N hydrochloric acid. Add sodium bicarbonate and then extract with 200ml of ether. Dry the ether extract and concentrate to obtain 7.8 g ofthe title compound as a white solid, m.p. 188°-190° C. The salts may beprepared by standard techniques such as by treatment of a solution ofthe free base in a suitable organic solvent, e.g. ether, with thedesired acid, e.g. hydrochloric, and then filtering off the precipitatedsalt. The hydrochloride salt melts at 147°-149° C.

EXAMPLE 22-[4-(hexafluoro-2-hydroxy-2-propyl)-N-methyl-anilino]-2-thiazoline

Combine 11.0 g p-(hexafluoro-2-hydroxy-2-propyl)-N-methylaniline (0.04mole) and 9.7 g 2-chloroethylisothiocyanate (0.08 mole) in 100 mlbenzene. Heat to reflux 3 hours and filter off solid. Dissolve in 300 mlwater, basify with sodium carbonate. Extract with ether then dry andconcentrate. Recrystallize residue from hexane-ether to give crystals,m.p. 160°-3° C. The fumarate salt, prepared in methanol, has m.p.175°-7° C.

EXAMPLE 3 2-[4-(hexafluoro-2H-2-propyl)-N-methylanilino]-2-oxazoline

To a solution of 1.6 g2-[4-(2-chlorohexafluoro-2-propyl)-N-methylanilino]-2-oxazolinebisulfate (0.003 mole) in 40 ml ethanol add 0.1 g 5% palladium oncharcoal. Shake 3 hours with hydrogen at 3 atm. pressure, filter andconcentrate. Partition between ethyl acetate and aqueous sodiumbicarbonate. Dry and concentrate the ethyl acetate. Treat the residualoil with 0.2 g orthophosphoric acid in methanol, dilute with ether andfilter to give the phosphate salt, m.p. 93°-7° C.

EXAMPLE 42-[4-(2-chlorohexafluoro-2-propyl)-N-methylanilino]-2-oxazoline

Add 5.5 g of a 57% solution of sodium hydride in mineral oil (0.13 mole)to a solution of 22.7 gN-(2-chloroethyl)-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-N'-methylurea(0.06 mole) in 100 ml 1,2-dimethoxyethane. Stir one hour and then addslowly 15.1 g thionyl chloride (0.13 mole). After one hour, pour onto800 ml water. Filter off the solid, dissolve in 200 ml methanol, anddecant from the mineral oil. To the methanol add 16 g sodium borohydride(0.4 mole). Concentrate and dissolve the residue in ether. Wash withwater and concentrate to give a cream solid. Dissolve the solid in 40 ml2N sulfuric acid and 40 ml methanol. Reflux 1 hour and concentratepartially. Partition between ethyl acetate and aqueous sodiumbicarbonate. Dry and concentrate the ethyl acetate. Treat the residualoil in ether with ethereal sulfuric acid and filter off the solid.Partition between ethyl acetate and aqueous sodium bicarbonate. Dry theethyl acetate, concentrate and distill, b.p. 123°-31° (0.1mm). Treat thedistillate in ether with ethereal sulfuric acid to give the bisulfatesalt, m.p. 143°-6° C.

EXAMPLE 52-[4-(hexafluoro-2-methoxy-2-propyl)-N-methylanilino]-2-oxazoline

Add 8.3 g K₂ CO₃ (0.06 mole) to a solution of 11.3 gN-(2-chloroethyl)-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-N'-methylurea (0.03 mole) and 17.0 g (0.12 mole) of methyliodide in 120 ml acetonitrile. Stir 4 days, filter, and concentrate thefiltrate. Dissolve the residue in ether and wash with water. Dry andconcentrate the ether. Boil the residue 1 hour in 100 ml 50% methanol.Concentrate and partition between ether and 1N hydrochloric acid.Neutralize the aqueous layer with sodium bicarbonate, extract withether, dry and concentrate the ether. Dissolve the oil in 10 ml methanoland treat with 2.0 g fumaric acid. Pour the solution into ether andfilter to give the fumarate salt, m.p. 89°-91° C.

EXAMPLE 62-[4-(2-acetoxyhexafluoro-2-propyl)-N-methylanilino]-2-oxazoline

Add 2.2 g 57% sodium hydride (0.05 mole) to a solution of 17.1 g2-[4-(hexafluoro-2-hydroxy-2-propyl)-N-methylanilino-]-2-oxazoline in150 ml 1,2-dimethoxyethane. After 1 hour, add 3.9 g acetyl chloride(0.05 mole). After 1 hour additional, filter and concentrate. Dissolvethe residue in ether and 1N hydrochloric acid. Neutralize the aqueouslayer with sodium bicarbonate. Extract with ether and dry over magnesiumsulfate. Treat the solution with etheral hydrochloric acid. Collect thesolid and recrystallize from methanol ether to give the hydrochloridesalt, m.p. 102°-4° C.

A number of agents are known in the treatment of hypertension. Certainof these, for example reserpine, are effective in lowering the bloodpressure in some patients but in other patients give rise to undesirableand well known side effects.

The compounds of the present invention have been found to exhibit usefuland potent anti-hypertensive activity. They produce rapid onset of suchactivity. Further, representative compounds of the invention have beenfound to be particularly active as anti-hypertensive agents whileavoiding or mitigating some of the deleterious side effects, such ascentral nervous system depression associated with knownanti-hypertensive agents. Based on laboratory tests, it is consideredthat the effective dosage (the ED₅₀) by oral administration for acompound of the present invention will typically lie within the range offrom 0.01 to 2 mg/kg of mammalian weight per day. For the preferredcompound,2-[4-hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline, thecontemplated daily human dose is about 0.6 to 10 mg.

The required daily dosage may be administered in single or divideddoses. The exact dose to be administered will, of course, be dependentupon where the compound in question lies within the above quoted dosageranges and upon the age and weight of the subject mammal.

The compounds are administered orally. In any event, a suitablepharmaceutical carrier is employed, with the carrier selected accordingto the physical properties of the compound in the pharmaceuticalcomposition. The carrier should not react chemically with the compoundto be administered. The preparations containing the active ingredientsmay typically be in the form of tablets, capsules, syrups, elixirs orsuspensions.

Representative formulations for the compounds of the general formula Iwill now be illustrated by way of the following Examples.

Tablet Formulations

    ______________________________________                                                               Milligrams                                             Formulation I          per Tablet                                             ______________________________________                                        2-[4-(hexafluoro-2-hydroxy-2-                                                 propyl)-N-methylanilino]-2-                                                   oxazoline              1                                                      Lactose, direct compression grade                                                                    222                                                    Microcrystalline cellulose                                                                           30                                                     Sodium Lauryl Sulfate  20                                                     Corn starch            25                                                     Magnesium stearate     2                                                                             300                                                    ______________________________________                                    

Mix together the stated active ingredient, lactose, microcrystallinecellulose, sodium lauryl sulfate and corn starch. Pass through a No. 40screen. Add the magnesium stearate, mix and compress into desired shapeon a tablet machine.

    ______________________________________                                                               Milligrams                                             Formulation II         per Tablet                                             ______________________________________                                        2-[4-(hexafluoro-2-hydroxy-2-                                                 propyl)-N-methylanilino]-2-oxazoline                                                                 1                                                      Lactose, U.S.P.        240                                                    Dicalcium phosphate    57                                                     Sodium Lauryl Sulfate  20                                                     Polyvinylpyrrolidine   10                                                     Water 50 ml/1000 tablets                                                      Corn Starch            20                                                     Magnesium Stearate     2                                                                             350                                                    ______________________________________                                    

Mix together the stated active ingredient, lactose, dicalcium phosphateand sodium lauryl sulfate. Screen the above mixture through a No. 60screen and granulate with an aqueous solution containingpolyvinylpyrrolidone. Add additional water, if necessary, to bring thepowders to a pasty mass. Add corn starch and continue mixing untiluniform granules are formed. Pass through a No. 10 screen, tray and dryin an oven at 40° C. for 12 to 14 hours. Reduce the dried granulationthrough a No. 16 screen. Add magnesium stearate, mix and compress intodesired shape on a tablet machine.

Capsule Formulations

    ______________________________________                                                               Milligrams                                             Formulation I          per Capsule                                            ______________________________________                                        2-[4-(hexafluoro-2-hydroxy-2-                                                 propyl)-N-methylanilino]-2-                                                                          1                                                      oxazoline                                                                     Lactose, U.S.P.        222                                                    Microcrystalline Cellulose                                                                           30                                                     Sodium Lauryl Sulfate  20                                                     Corn Starch            25                                                     Magnesium Stearate     2                                                                             300                                                    ______________________________________                                    

Procedure

Mix together the stated active ingredient, lactose, microcrystallinecellulose, sodium lauryl sulfate and corn starch. Pass through a No. 80screen. Add the magnesium stearate, mix and encapsulate into the propersize two-piece gelatin capsule.

In treating certain patients with the compounds of this invention it maybe desirable to include other pharmaceutically active ingredients in thesame dosage unit. For example, in treating patients in whom salt andwater retention is a problem, effective amounts of conventionaldiuretics can be incorporated, such as the thiazide diuretics, e.g.hydrochlorothiazide or trichloromethiazide. Similarly, in treatingpatients in whom tachycardia might be a problem, an effective amount ofa pharmaceutically acceptable beta-blocking agent can be included, e.g.propnanolol. The dosage unit could even contain a combination of acompound of this invention, e.g.2-[4-(hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline, adiuretic, e.g. hydrochlorothiazide and a beta-blocker, e.g. propnanolol.

Numerous other variants of the above compounds, compositions and methodswill be apparent to one skilled in the art within the scope of thisinvention.

I claim:
 1. A compound of the formula ##STR4## wherein X is a sulfuratom,R is alkyl having 1 to 4 carbon atoms, R₁, r₂ and R₃ areindependently hydrogen, bromine, chlorine, fluorine, lower alkyl, loweralkoxy, lower alkanoyloxy or nitro, Y, y₁, y₂ and Y₃ are independentlyhydrogen, chlorine or fluorine, Z is independently hydrogen, hydroxy,lower alkoxy, lower alkanoyloxy, chlorine or fluorine, and thepharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1 wherein R is methyl.
 3. A compound according to claim 1 whereinR₁, R₂ and R₃ are each hydrogen.
 4. A compound according to claim 1wherein Z is hydroxy.
 5. A compound according to claim 1 wherein R₃ ishydrogen.
 6. A compound according to claim 5 wherein R₁ and R₂ are eachlower alkyl.
 7. A compound according to claim 1 wherein Y, Y₁, Y₂ and Y₃are each fluorine.
 8. A compound according to claim 7 wherein Z ishydroxy.
 9. A compound according to claim 1 wherein X is sulfur.
 10. Acompound according to claim 9 wherein Z is hydroxy.
 11. A compoundaccording to claim 10, said compound being2-[4-(hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]-2-thiazoline. 12.A pharmaceutical composition adopted to treat hypertension comprising anoral dosage of an antihypertensively effective amount of a compound ofclaim 1 in a pharmaceutically acceptable diluent.
 13. A compositionaccording to claim 12 in the form of a solid oral dosage unit.
 14. Amethod of treating hypertension comprising orally administering to ahypertensive mammal a composition of claim 12.